The treatment of proliferative disease, particularly cancer, by chemotherapeutic means often relies upon exploiting differences in target proliferating cells and other normal cells in the human or animal body. For example, many chemical agents are designed to be taken up by rapidly replicating DNA so that the process of DNA replication and cell division is disrupted. Another approach is to identify antigens on the surface of tumour cells which are not normally expressed in developed human tissue, such as embryonic antigens. Such antigens can be targeted with binding proteins such as antibodies to deliver a toxic agent to or other substance which is capable directly or indirectly of activating a toxic agent at, the site of a tumour.
An alternative approach which has been developed more recently relies on the fact that a significant proportion of tumour cells are in various stages of cell degeneration and death. Unlike programmed cell death (apoptosis) which occurs during the natural turnover of certain cell types, tumour cells undergo a degenerative and less controlled death during which they have been found to exhibit abnormal surface membrane permeability. European patent application EP-A-270340 describes the preparation of murine antibodies to nuclear components of cells which are able to target necrotic cells in a tumour by exploiting this phenomenon. Miller et al (Hybridoma, 1993, 12, 689-697) describe a particular antibody prepared in accordance with EP-A-270340. This antibody, TNT-1, was found to bind histone fraction H1. The histones are the most abundant proteins in chromatin, the concentration of each type of histone being approximately 5000 times higher than the concentration of a typical sequence-specific DNA-binding protein. Epstein et al (in “Handbook of Targeted Delivery of Imaging Agents” CRC press, Inc., 1995, ed. VP Torchilin) describes the uptake of radiolabelled TNT-1 into nude mice bearing the ME-180 cervical carcinoma, and report that there was no appreciable labelling of other organs. The authors also used the F(ab′)2 fragment of TNT-1 labelled with 131I for tumour imaging studies in human patients.
A known problem with the use of murine antibodies in human therapy is that repeat treatment of such antibodies leads to a human anti-mouse antibody (HAMA) response. HAMA responses have a range of effects, from neutralisation of the administered antibody leading to a reduced therapeutic dose, through to allergic responses, serum sickness and renal impairment. In order to overcome these disadvantages humanization of antibodies has been developed. More recently, repertoires of human antibodies have been cloned and these can be screened, for example by phage display technology, (McCafferty et al, WO92/01047) to identify human antibodies specific for human antigens.